16,17 acetals of pregnane derivatives and pharmaceutical compositions containing them

ABSTRACT

@ A process for the preparation of 16,17 acetals of pregnane derivatives by trans-ketalization of 16,17-acetonides is described.In the instance of the preparation of 16a,17a-butylide- nedioxy-11β,21-dihydroxypregna-1,4-diene-3,20-dione, a compound having useful therapeutic properties, known also as budesonide, it is possible to obtain the more active epimer with high selectivity and remarkable economic advantages in comparison with the known methods.New 16,17 acetals of pregnane derivatives, which can be prepared by the method of the invention, are also described.

This application is a continuation-in-part of appl. ser. no. 739,131 filed May 30, 1985, now U.S. Pat. No. 4,695,625.

The present invention relates to 16,17 acetals of pregnane derivatives and to pharamceutical compositions containing them.

The 16,17 acetals of pregnane derivatives according to this invention have the following general formula: ##STR2## wherein R₁ is CH₃ (CH₂)₂ CH--, R₂ and R₃ are separately selected from H and Hal, and X is H, Hal or CH₃ COO--. Specifically, the compounds according to this invention are the following:

9α-fluoro-21-chloro-16α,17α-butylidenedioxy-11β-hydroxypregna-4-ene-3,20-dione;

6α-fluoro-16α,17β-butylidenedioxy-11β,21-dihydroxypregna-4-ene-3,20-dione;

960 -fluoro-16α,17α-butylidenedioxy-11β,21-dihydroxypregna-4-ene-3,20-dione;

6α-fluoro-9α-chlor0-16α,17α-butylidenedioxy-11.beta.-hydroxy,

21-acetoxy-pregna-4-ene-3,20-dione.

The compounds of this invention can be prepared by reacting 16,17-acetonides with aldhydes having the formula R₁ CHO, in which R₁ has the meaning given above, in molar ratios ranging from 1:1 to 1:5, preferably from 1:1 to 1:1.1, in aqueous hydrofluoric acid and concentrations ranging from 20 to 90%, preferably from 50 to 70%, at a temperature from -70° to 20° C., the temperature being choosen in order to give the desired epimer ratio.

The product is isolated by simple water dilution, in high purity.

Although working with unitary stoichiometric ratios between the steroidal substrate and the carbonyl compound, the reaction takes place in almost quantitative yields.

Alternatively, instead of hydrofluoric acid, it is possible to use hydrochloric acid. In this case, however, the reaction is less selective in the isomers ratio and the product obtained is less pure.

It should be noted that the acetonide can be replaced by the corresponding diol derivative. Under these conditions the acetal is always produced with an excess of the B epimer, but with a lower selectivity.

Another aspect of the invention, equally important, concerns the conversion of the less active epimer of a 16,17-acetal into the more active epimer. For instance, a mixture of budesonide containing only 30% of the B epimer, subjected to the above mentioned conditions for the preparation of budesonide from the corresponding acetonide, is transformed into budesonide having more than 90% of B epimer. This process is very useful to recover active product from the mother liquors (as deriving from the crystallization) enriched in A epimer. For the epimerization of budesonide like compounds it is sufficient the treatment with hydrofluoric acid alone but, usually, an amount (lower than the stoichiometric one) of the aldehyde (in the instance of budesonide, butyraldehyde) is added in order to avoid any formation of the 16,17-diol.

The following non limiting examples further illustrate the invention. The designation "A epimer" or "B epimer" is made according to U.S. Pat. No. 3,928,326 and the epimer ratio was determined by HPLC using a reversed phase RP-18 column, eluting with 40% acetonitrile.

EXAMPLE 1

50 Grams of desonide (16β-hydroxyprednisolone-16,17-acetonide) and immediately thereafter 12,5 ml of butyraldehyde were added to 500 ml of a 70% hydrofluoric acid solution, at -5° C. The mixture was stirred at 0° C. for one hour and then poured into 5 liters of demineralized water at 0° C. The precipitate was filtered, washed to neutrality with water and dried under vacuum to give 51 g of pure budesonide with an A/B epimer ratio of 9/91.

EXAMPLE 2

The procedure described in Example 1 was repeated, except that the desonide was replaced by other acetonides. The corresponding acetals with butyraldehyde were obtained in almost quantitative yields and with the epimer ratios reported in the following Table I.

                                      TABLE I                                      __________________________________________________________________________                                         Ratio A/B                                  Compound                                                                             Starting product                                                                            Final product    epimer                                     __________________________________________________________________________     2a    Desonide 21-acetate                                                                         Budesonide 21-acetate                                                                           13/87                                      2b    Triamcinolone acetonide                                                                     9α-Fluoro-budesonide                                                                      15/85                                      2c    Fluocinolone acetonide                                                                      6α,9α-Difluoro-budesonide                                                           11/89                                      2d    Flunisolide  6α-Fluoro-budesonide                                                                      (Apparen-                                                     (6α-Fluoro-16α, 17α-butyli-                                                   tly only                                                      denedioxy-11β, 21-dihydroxy-                                                               one epimer)                                                   pregna-1,4-diene-3,20-dione)                                2e    Flurandrenolide                                                                             6α-Fluoro-16α,17α-butylidene-                                                 (Apparen-                                                     dioxy-11β,21-dihydroxypregna-                                                              tly only                                                      4-ene-3,20-dione one epimer)                                2f    Alcinonide   9α-Fluoro-21-chloro-16α,17α-                                                  12/88                                                         butylidenedioxy-11β-hydroxy-                                              pregna-4-ene-3,20-dione                                     2g    9α-Fluoro-16α,17α-iso-                                                    9α-Fluoro-16α,17α-butylidenedio-                                               9/91                                            propylidenedioxy-11β,21-                                                               xy-11β,21-dihydroxypregna-4-                                 dihydroxy-pregna-4-ene-                                                                     ene-3,20-dione                                                    3,20-dione                                                               2h    21-Acetoxy-16α,17α-                                                             21-Acetoxy-16α,17α-butylidene-                                                      10/90                                            isopropylidenedioxy-                                                                        dioxy-11β-hydroxypregna-4-ene-                               11β-hydroxypregna-                                                                     3,20-dione                                                        4-ene-3,20-dione                                                         2i    6α-Fluoro-9α-chloro-                                                            6α-Fluoro-9α-chloro-budesonide                                                      10/90                                            desonide 21-acetate                                                                         21-acetate                                                  2j    Fluocinonide 6α,9α-Difluoro-budesonide                                                           ca. 15/85                                                     21-acetate                                                  __________________________________________________________________________

EXAMPLE 3

The procedure described in Example 1, was repeated, except that the reaction was carried out at -78° (and quenching the reaction after 12 hours at this temperature). Budesonide was obtained (A/B ratio 47/53) together with unreacted desonide (about 40%).

EXAMPLE 4

The procedure described in Example 1 was repeated, substituting butyraldehyde by isobutyraldehyde. 16α-Hydroxyprednisolone 16,17-acetal, apparently only one epimer, was obtained.

EXAMPLE 5

Under the same conditions as in Example 1, but using 16α-hydroxyprogesterone instead of desonide, budesonide was obtained (A/B ratio 16/84).

EXAMPLE 6

Under the same conditions as in Example 1, but using budesonide (A/B ratio 70/50) instead of desonide, budesonide having A/B ratio of 10/90 was obtained.

EXAMPLE 7

To illustrate the topical anti-inflammatory efficacy of the new compounds according to the present invention, the compounds identified in Table I as 2e, 2f and 2g were compared to the compound of Example 3 of U.S. Pat. No. 4,404,200. The compounds were compared on the basis of their ability to inhibit cotton-pellet induced granulomas (concentration necessary for 50% inhibition, method of Meier, Experientia, 6, 469, 1950). Results appear in the following Table II.

                  TABLE II                                                         ______________________________________                                                        Relative Topical                                                               Anti-Inflammatory Potency                                       Compound       (Budesonide = 1)                                                ______________________________________                                         Ex. 3 USP 4,404,200                                                                           0.39                                                            2e             3.03                                                            2f             4.86                                                            2g             1.80                                                            ______________________________________                                    

EXAMPLE 8

Compound 2i of Table I was similarly compared to the compound of Example 22 of U.S. Pat No. 3,983,233. Results appear in the following Table III.

                  TABLE III                                                        ______________________________________                                                        Relative Topical                                                               Anti-Inflammatory Potency                                       Compound       (Budesonide = 1)                                                ______________________________________                                         Ex. 22 USP 3,983,233                                                                          1.49                                                            2i             5.90                                                            ______________________________________                                    

The present invention also relates to a method for the treatment of inflammatory conditions using a pharmaceutical composition comprising an effective amount of a compound as herein described together with a pharmaceutically acceptable carrier. Pharmaceutical dosage forms are prepared according to procedures well known in the art and, where suitable, the compositions as herein described may contain other active ingredients, e.g., antibiotics.

The following examples illustrate topical formulations prepared in accordance with this invention:

    ______________________________________                                         (a) Inhalation Aerosol                                                             9α-Fluoro-21-chloro-16α,17α-butylidene-                                               1-10     mg                                           dioxy-11β-hydroxypregna-4-ene-3,2-dione                                   Oleic Acid               0.5      mg                                           Trichlorofluormethane    3000     mg                                           Diclorofluormethane      7500     mg                                       (b) Lotion                                                                         6α-Fluoro-16α,17α-butylidenedioxy-11β,21-                                        0.05-5.0 mg                                           dihydroxypregna-4-ene-3,20-dione                                               (Compound 2e)                                                                  Ethyl alcohol            400      mg                                           Polyethyleneglycol 400   300      mg                                           Hydroxypropyl cellulose  5        mg                                           Propylene glycol         300      mg                                       (c) Glycol Ointment                                                                9α-Fluoro-16α,17α-butylidenedioxy-11β,21-                                        0.05-5.0 mg                                           dihydroxypregna-4-ene-3,20-dione                                               (Compound 2g)                                                                  Hexylene glycol          100      mg                                           Propylene glycol monstearate                                                                            20       mg                                           White wax                60       mg                                           White petrolatum         880      mg                                       (d) Cream                                                                          6α-Fluor-9α-chloro-16α,17α-butylidene-                                          10-100   mg                                           dioxy-11β-hydroxy, 21-acetoxy-pregna-4-                                   ene-dione (Compound 2i)                                                        Propylene glycol         47.5     mg                                           Glyceryl monostearate self-emulsifying                                                                  1.5      mg                                           Glyceryl monostearate    10.5     mg                                           Cetostearylic alcohol    8.0      mg.                                          White beeswax            1.25     mg                                           Chlorocresol (4-chloro-3-methylphenol)                                                                  0.075    mg                                           Sodium citrate           0.05     mg                                           Citric acid              0.05     mg                                           Purified water q.s. to   100      mg                                       ______________________________________                                     

I claim:
 1. A compound according to the formula ##STR3## in which X is H, Hal or CH₃ COO-; R₁ is CU₃ (CH₂)₂ CH-; and R₂ and R₃ are separately H or Hal.
 2. A pharmaceutical composition having anti-inflammatory properties comprising as the active ingredient an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier.
 3. A method of treating inflammatory conditions which comprises administering to a patent an anti-inflammatory effective amount of a composition according to claim
 2. 4. 9α-Fluoro-21-chloro-16.alpha.,17β-butylidenedioxy-11β-hydroxypregna-4-ene-3,20-dione.
 5. A pharmaceutical composition having antiinflammatory properties comprising as the active ingredient an effective amount of the compound according to claim 4 together with a pharmaceutically acceptable carrier.
 6. A method of treating inflammatory conditions which comprises administering to a patient an anti-inflammatory effective amount of a composition according to claim
 5. 7. 6α-Fluoro-16α,17.beta.-butylidenedioxy-11α,21-dihydroxypregna-4-ene-3,20-dione.
 8. A pharmaceutical composition having antiinflammatory properties comprising as the active ingredient an effective amount to the compound according to claim 7 together with a pharmaceutically acceptable carrier.
 9. A method of treating inflammatory conditions which comprises administering to a patient an anti-inflammatory effective amount of a composition according to claim
 8. 10. 9α-fluoro-16α,17.alpha.-butylidenedioxy-11β,21-dihydroxypregna-4-ene-3,20-dione.
 11. A pharmaceutical composition having anti-inflammatory properties comprising as the active ingredient an effective amount of the compound according to claim 10 together with a pharmaceutically acceptable carrier.
 12. A method of treating inflammatory conditions which comprises administering to a patient an anti-inflammatory effective amount of a composition according to claim
 11. 13. 6α-Fluoro-9α-chloro-16α,17β-butylidenedioxy-11β-hydroxy, 21-acetoxy-pregna-4-ene-3,20-dione.
 14. A pharmaceutical composition having antiinflammatory properties comprising as the active ingredient an effective amount of the compound according to claim 13 together with a pharmaceutically acceptable carrier.
 15. A method of treating inflammatory conditions which comprises administering to a patient an anti-inflammatory effective amount of a composition according to claim
 14. 